WO2005075497A1

WO2005075497A1 - PROCESS FOR THE PREPARATION OF 17ß-SUBSTITUTED-3-OXO-4-AZA-5ALPHA-ANDROSTANE DERIVATIVES

Info

Publication number: WO2005075497A1
Application number: PCT/IB2004/004117
Authority: WO
Inventors: Yatendra Kumar; Rakesh Singh; Saridi Madhava Dileep Kumar; Keshav Deo; Swargam Sathyanarayana
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-01-07
Filing date: 2004-12-14
Publication date: 2005-08-18

Abstract

Process for the preparation of 17ß-substituted-3-oxo-4-aza-5α-androstane derivatives, which are useful intermediates for the synthesis of 3-oxo-4-aza-5α-androst-1-ene derivatives including finasteride, is provided.

Description

PROCESS FOR THE PREPARATION OF 17£-SUBSTITUTED-3-OXO-4-AZA-5α- ANDROSTANE DERIVATIVES

Field of the Invention The present invention relates to a process for the preparation of 17/3-substituted-3- oxo-4-aza-5α-androstane derivatives, which are useful intermediates for the synthesis of 3- oxo-4-aza-5α-androst-l-ene derivatives including fmasteride. Background of the Invention Chemically, fmasteride is N-tert-butyl-3-oxo-4-aza-5o;-androst-l-ene-17/3- carboxamide and is known from U.S. Patent No. 4,760,071. It is a 5α-reductase inhibitor, which functions in many andro gen-sensitive tissues by converting the major circulating androgenic hormone, testosterone, into the intracellular androgenic metabolite dihydrotestosterone (DHT). Finasteride is used in the treatment of hyperandrogenic conditions, such as acne vulgaris, seborrhea, female hirsutism and benign prostate hypertrophy. Several processes have been reported for the preparation of finasteride such as U.S. Patent Nos. 4,377,584; 4,760,071; 5,084,574; 5,237,061; 5,120,847; 5,670,643; 5,021,575; and 6,509,466; published PCT Application No. WO 02/46207; J Med. Chem., (1986), 29, pp. 2298-2315; J. Med. Chem., (1984), 27, pp. 1690-1701; and Heterocycles, (1998), 47, p. 703. All the reported references disclose the conversion of 17/3-substituted-5-oxo-A- nor-3,5-secoandrostane-3-oic acid to 17/3-substituted-3-oxo-4-aza-5θ!-androstane derivative in two steps. J Med. Chem., (1984), 27, p. 1690 and U.S. Patent No. 4,377,584 disclose the use of methylamine in the presence of ethylene glycol or ethanol for the ring closure of 17/?-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acid to 173-substituted- 3-oxo-4-methyl-4-aza-5α:-androst-5-ene derivative, whereas the process of J Med. Chem., (1986), 29, p. 2298 uses liquid ammonia. In all the above references, the product was isolated and then hydrogenated in the presence of platinum oxide in acetic acid to obtain 17/3-substituted-3-oxo-4-aza-5α-androstane derivative. Heterocycles, (1998), 47, p. 703 reports the use of ammonium acetate in the presence of acetic acid for the ring closure reaction and the product was isolated, which was then hydrogenated in the presence of palladium-carbon in acetic acid to obtain 17/?-substituted-3-oxo-4-aza-5θ!-androstane derivative. An alternate method for reducing 17/3-substituted-3-oxo-4-aza-5α;-androst-5- ene derivative is given in Heterocycles, (1998), 47, p. 703 in which formic acid and potassium carbonate are used in dimethylformamide for reduction to obtain the 17/3- substituted-3-oxo-4-aza-5α-androstane derivative. WO 02/46207 teaches the use of ammonium salt of lower alkyl carboxylic acids in the catalytic hydrogenation process. J Med. Chem., (1984), 27, p. 1690 and U.S. Patent No. 4,377,584 disclose the preparation of N-alkyl-3-oxo-5α-androst-4-ene-17/3-carboxamide comprising reacting 3- oxo-5α-androst-4-ene-17/3-carboxylic acid with oxalyl chloride, pyridine and corresponding alkyl amine. Heterocycles, (1998), 47, p. 703 discloses the use of thionyl chloride, pyridine and corresponding alkyl amine for the preparation of N-alkyl-3-oxo-4- aza-5α-androst-4-ene-17/3-carboxamide. WO 03/27132 reports the use of pivaloyl chloride with tertiary butyl amine in the presence of a base for the conversion of androst- 4-en-3-one-17/3-carboxylic acid to 17/3(N-tert-butylcarbamoyl)-androst-4-ene-3-one.

Summary of the Invention In one aspect is provided a simplified process for the preparation of 17/3- substituted-3-oxo-4-aza-5-α:-androstane derivative of Formula I,

Formula I wherein R represents hydrogen; hydroxyl; C_1-6 straight or branched chain alkyl; Cι_-6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, Cι_-6 straight or branched chain alkyl, aryl or arylalkyl. The process can include reacting a compound of Formula II

Formula II wherein R is as defined above, with an ammonium salt in a solvent followed by further reaction after addition of formic acid. In another aspect are provided processes for the preparation of N-alkyl-3-oxo-4- aza-5α-androst-4-ene-17/3-carboxamide of Formula III,

Formula III wherein Ri represents Cι_-6 straight or branched chain alkyl, comprising reacting 3-oxo-4- aza-5-Q!-androstene-17(3-carboxylic acid of Formula IN

Formula IV with phosphorous oxychloride and alkyl amine of Formula R]ΝH₂, wherein Ri is as defined above in the presence of pyridine. The process provided herein can be simplified to the point of avoiding the isolation of intermediate compounds - the so-called "one-pof reaction. Detailed Description of the Invention The simplified synthesis of compound of Formula I from the compound of Formula II gives good yields and avoids time consuming workup procedures used for isolating 17/3-substituted-3-oxo-4-aza-5α-androst-5-ene derivative of Formula VI

Formula VI wherein R can be hydrogen; hydroxyl; Cι_-6 straight or branched chain alkyl; Cι_-6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, Cι_-6 straight or branched chain alkyl, aryl or arylalkyl. In some particular examples R represents N-tertiary-butyl carboxamide. Examples of ammonium salts include ammonium formate, ammonium acetate, ammonium propionate, ammonium sulfate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium chloride, ammonium bromide, ammonium iodide and ammonium fluoride. Suitable solvents for the reaction of compounds of Formula II with ammonium salt are inert organic solvents that do not undergo chemical change under the reaction conditions. Examples of such solvents include glycols such as ethylene glycol or propylene glycol; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof. Temperatures for the reaction of compound of Formula II with ammonium salt are not critical and the reaction may be performed at temperatures of from about room temperature to about 220°C. The reaction may be performed at temperatures of from about 150°C to about 180°C in some particular embodiments. In the preparation of N-alkyl-3-oxo-4-aza-5α:-androst-4-ene-17/3-carboxamide, examples of the alkyl group of the alkyl amine can include Cι_-6 straight or branched chain alkyl group. In some particular embodiments, tertiary butyl amine is used. The reaction of compounds of Formula IN with phosphorous oxychloride, pyridine and alkyl amine may performed in inert solvents. Examples of such solvents include hydrocarbons such as benzene, xylene, toluene, heptane, hexane, cyclohexane or octane; alkyl ethers such as diethylether, diisopropylether or dimethoxyethane; alcohols such as methanol, ethanol or isopropanol; ketones such as acetone or methyl ethyl ketone; chlorinated hydrocarbons such as methylene chloride, ethylene dichloride or carbon tetrachloride; esters such as ethylacetate or isopropylacetate; nitriles such as acetonitrile or benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide or dimethylformamide; cyclic ethers such as dioxane or tetrahydrofuran; and mixtures thereof. Temperatures for the reaction of compound of Formula IN with phosphorous oxychloride, pyridine and alkyl amine may be in the range of from about -10°C to about room temperature. The reaction may be performed at temperatures of from about -10°C to about 10°C in some particular embodiments. 17/3-substituted-5-oxo-A-nor-3,5-secoandrostane-3-oic acids of Formula II may be prepared by conventional methods such as these described in prior art including, for example, Heterocycles, 1998, 47, 703; WO 02/46207 and US 4,377,584, which are incorporated herein by reference. In general, it may be prepared by oxidizing 17/3- substituted-3-oxo-4-aza-5cκ-androst-4-ene-derivatives, for example with sodium periodate and potassium permanganate, or using ozone. In some particular embodiments 17/3- substituted-3-oxo-4-aza-5o!-androst-4-ene-derivative may be the compound of Formula VII,

Formula VII wherein R] is as defined above, which may be prepared from oxidation of compound of Formula III. The compound of Formula III, in turn, may prepared by the process comprising reacting compound of Formula IV with phosphorous oxychloride and alkyl amine of Formula RιNH , wherein Ri is as defined above in the presence of pyridine, as described herein. 17/3-substituted-3-oxo-4-aza-5θ!-androstane derivative of Formula I may be further converted to 3-oxo-4-aza-5-α-androst-l-ene derivative of Formula V,

Formula V wherein R is as defined above, by methods described in the literature including U.S. Patent Nos. 5,120,847; 5,084,574; 5,021,575; WO96/12034; J Med. Chem., 1986, 29, p. 2298; and J. Med. Chem., 1984, 27, p. 1690, which are incorporated herein by reference. In general, it may be converted by refluxing the compound of Formula I with benzeneseleninic anhydride in chlorobenzene. In the following section embodiments are described by way of examples to illustrate the process provided herein. However, these do not limit the scope of the present invention. EXAMPLES

Example 1: Preparation of N-tert-butyl-3-oxo-5α-androst-4-ene-17β-carboxamide A solution of 3-oxo-4-androst-4-ene-17β-carboxylic acid (50 g, 2.37 mmol) in toluene (700 ml) was refluxed azeotropically to remove moisture. The reaction mixture was then cooled to room temperature and pyridine (13 g, 2.411 mmol) was added to it. It was thereafter cooled to 0 to 5°C and treated with phosphorous oxychloride (32 g, 3.13 mmol), maintaining anhydrous condition under nitrogen atmosphere. After addition, the reaction mixture was heated to room temperature and stirred for 3 hours. Tertiary butylamine (159.9 g, 19.989 mmol) was then added at 0 to 5°C and was stirred for 15 minutes. It was then heated to room temperature and was stirred for 3 hours. Reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered through hyflo and filtrate was washed twice with distilled water (500 ml each) and 10% aqueous sodium chloride solution (500 ml each). Toluene was recovered completely under reduced pressure at 40-45°C and residue was treated with hexane (197 ml) to crystallize the title product. The product was filtered, washed with hexane (50 ml) and dried under reduced pressure. Yield: 54.8 g

Example 2: Preparation of 17β-(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5- secoandrostane-3-oic acid A solution of N-tert-butyl-3-oxo-5α-androst-4-ene-17β-carboxamide (50 g, 2.153 m mol) in a mixture of tertiary butanol (1.5 1) and aqueous solution of sodium carbonate (22 g in 80 ml distilled water) was treated with a solution of sodium periodate (200 g,

14.961 mmol) and potassium permanganate (2 g, 0.202 mmol) in distilled water (1.5 1) at 35 - 45°C. The reaction mixture was stirred for 12 hour at 35 - 45°C. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was filtered and the filtrate was again treated with sodium carbonate (2 g) and filtered. Tertiary butanol was recovered under reduced pressure at 50- 60°C. The concentrated mixture was diluted with distilled water (750 ml). It was then treated with activated carbon (5 g), filtered through hyflo and filtrate was treated with 6N-hydrogen chloride (pH ~2) to precipitate the title product. The product was filtered, washed with distilled water and dried under reduced pressure. Yield: 40.1 g

Example 3: Preparation of N-tert-butyl-3-oxo-4-aza-5α-androstane-17β-carboxamide via N-tert-butyl-3-oxo-4-aza-5α-androst-4-ene-17β-carboxamide A solution of 17β-(N-tert-butyl) carbamoyl-5-oxo-A-nor-3,5-secoardrostane-3-oic acid (50 g, 1.532 mmol) and ammonium formate (100 g, 19.029 mmol) in ethylene glycol (375 ml) was stirred at room temperature for 2 hours. The reaction mixture was gradually heated to 160 - 170°C and was stirred for 4 hours. The reaction was monitored by TLC. After completion of reaction, formic acid (150 ml) was added at 70 - 80°C. After addition of formic acid, the reaction mixture was gradually heated to 140 - 150°C and was stirred for 12 hours. The reaction was monitored by TLC. After completion of reaction, the reaction mixture was quenched by distilled water (1.75 1) and stirred for 30 minutes. The product crystallized out at this stage. The product was filtered and washed with distilled water. This wet solid was dissolved in dichloromethane (350 ml) and water layer was separated. Dichloromethane solution was then treated with activated carbon (5 g). It was filtered through hyflo and dichloromethane was recovered completely under reduced pressure at 35 - 40°C. The residue was stirred with ethyl acetate to crystallize the product. The product was filtered, washed with ethyl acetate and dried under reduced pressure. Yield: 19.4 g

Example 4: Preparation of N-tert-butyl-3-oxo-4-aza-5α-androst-l-ene-17β-carboxamide (Finasteride) A suspension of N-tert-butyl-3-oxo-4-aza-5α-androstane-17β-carboxamide (50 g, 0.534 mmol) and benzeneseleninic anhydride (100 g, 1.11 mmol) in toluene (1.5 1) was refluxed for 18 hours at 110 - 112°C. The reaction was monitored by HPLC or TLC.

After completion of reaction, toluene was completely recovered under reduced pressure at 45 - 55°C. The resulting residue was dissolved in dichloromethane (600 ml) and washed twice with 10% aqueous sodium hydroxide solution and then with 10% aqueous sodium chloride solution. The dichloromethane layer was separated, concentrated and residue was crystallized by refluxing it with hexane for 30 minutes. The above hot mixture was filtered at 60 - 65°C and obtained solid was washed with hot hexane. This wet solid was dissolved in dichloromethane (400 ml) and again washed with 10% aqueous sodium hydroxide and 10% aqueous sodium chloride solution. The dichloromethane layer was separated and treated with activated carbon (5 g) and neutral alumina (10 g). It was then filtered through hyflo and dichloromethane was recovered completely from the filtrate under reduced pressure at 35 - 40°C. The residue was crystallized by refluxing it in hexane for 30 minutes. The hot mixture was filtered at 60 - 65°C, washed with hot hexane and dried under reduced pressure. Yield: 25.6 g

Claims

We claim:

1. A process for the preparation of 17/3-substituted-3-oxo-4-aza-5α-androstane derivative of Formula I,

Formula I wherein R represents hydrogen; hydroxyl; Cι_-6 straight or branched chain alkyl; Cι_-6 straight or branched chain alkoxy; aryl; or NHA wherein, A represents hydrogen, Cι_-6 straight or branched chain alkyl, aryl or arylalkyl; the process comprising reacting a compound of Formula II

Formula II wherein R is as defined above, with an ammonium salt followed by addition of formic acid.

2. A process for the preparation of N-alkyl-3-oxo-4-aza-5α;-androst-4-ene- 17/3- carboxamide of Formula III,

Formula III wherein Ri represents Cι_-6 straight or branched chain alkyl, comprising reacting 3-oxo-4- aza-5c.-androstene-17/3-carboxylic acid of Formula IV

Formula IV with phosphorous oxychloride and alkyl amine of Formula R[NH₂, wherein Ri is as defined above in the presence of pyridine

3. The process according to claim 1, wherein R is N-tertiary-butyl carboxamide.

4. The process according to claim 1, wherein ammonium salt is selected from the group consisting of ammonium formate, ammonium acetate, ammonium propionate, ammonium sulfate, ammonium persulfate, ammonium sulfide, ammonium phosphate, ammonium nitrite, ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium chlorate, ammonium chloride, ammonium bromide, ammonium iodide and ammonium fluoride.

5. The process according to claim 1, wherein suitable solvent is selected from the group consisting of glycols, alkyl ethers, alcohols, ketones, chlorinated hydrocarbons, esters, nitriles, dipolar aprotic solvents, cyclic ethers and mixtures thereof.

6. The process according to claim 5, wherein glycol is selected from the group consisting of ethylene glycol, propylene glycol and mixtures thereof.

7. The process of preparing compound of Formula I according to claim 1, wherein the compound of Formula II is compound of Formula VII,

Formula VII wherein Ri is as defined above.

8. The process of preparing compound of Formula I according to claim 7, wherein the compound of Formula VII is prepared by oxidizing the compound of Formula III.

9. The process of preparing compound of Formula I according to claim 8, wherein the compound of Formula III is prepared by the process of claim 2.

10. The process according to claim 2, wherein the reaction is performed in an inert solvent, selected from the group consisting of alkyl ethers, alcohols, ketones, nitriles, chlorinated hydrocarbons, esters, hydrocarbons, dipolar aprotic solvents, cyclic ethers and mixtures thereof.

11. The process according to claim 10, wherein the hydrocarbon is selected from the group consisting of benzene, xylene, toluene, heptane, hexane, cyclohexane, octane and mixtures thereof.

12. The process as claimed in claim 1 or 9, further comprising conversion of compound of Formula I, wherein R is as defined above to compound of Formula V,

Formula V wherein R is as defined above.

13. The process as claimed in claim 12, wherein the conversion to compound V is achieved by the reaction of compound of Formula I with benzeneseleninic anhydride.

14. The process as claimed in claim 12, wherein compound of Formula V is N-tertiary- butyl-3-oxo-4-aza-5α:-androst-l-ene-17/3-carboxamide.

15. The process of claim 1, which is a one-pot process.